Oncotarget

Research Papers:

FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies

Antonio Martínez-Aranda _, Vanessa Hernández, Emre Guney, Laia Muixí, Ruben Foj, Núria Baixeras, Daniel Cuadras, Víctor Moreno, Ander Urruticoechea, Miguel Gil, Baldo Oliva, Ferran Moreno, Eva González-Suarez, Noemí Vidal, Xavier Andreu, Miquel A. Seguí, Rosa Ballester, Eva Castella and Angels Sierra

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Oncotarget. 2015; 6:44254-44273. https://doi.org/10.18632/oncotarget.5471

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Abstract

Antonio Martínez-Aranda1,2, Vanessa Hernández1, Emre Guney3, Laia Muixí1, Ruben Foj1,2, Núria Baixeras4, Daniel Cuadras5, Víctor Moreno5, Ander Urruticoechea6, Miguel Gil7, Baldo Oliva3, Ferran Moreno8, Eva González-Suarez9, Noemí Vidal4, Xavier Andreu10, Miquel A. Seguí11, Rosa Ballester12, Eva Castella13, Angels Sierra1,14

1Biological Clues of the Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L’Hospitalet de Llobregat, Barcelona, Spain

2Universitat Autònoma de Barcelona (UAB), Biochemistry and Molecular Biology Department, Faculty of Biosciences, Campus Bellaterra, Edifici C, Cerdanyola del Vallés, 08193 Barcelona, Spain

3Structural Bioinformatics Laboratory, Experimental Sciences Department, Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine, 08003 Barcelona, Spain

4Servei d’Anatomia Patològica, Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

5Biomarkers and Susceptibility Unit, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

6Breast Cancer Unit and Neuroncology Unit, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

7Oncology Service, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

8Radiation Oncology Service, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

9Transformation and Metastasis Group, Cancer Epigenetics and Biology Department, IDIBELL, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

10Pathology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain

11Oncology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain

12Radiation Oncology Service, Institut Català d’Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain

13Pathology Service, Institut Català d’Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain

14Molecular and Translational Oncology Laboratory, Biomedical Research Center CELLEX-CRBC Institut d’Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS 08036 Barcelona, Spain

Correspondence to:

Angels Sierra, e-mail: asierrajim@gmail.com, masierra@clinic.ub.es

Keywords: biomarkers, brain metastasis, breast cancer, FN14, GRP94

Received: April 17, 2015     Accepted: October 09, 2015     Published: October 19, 2015

ABSTRACT

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83–9.71) and 2.55- (95%CI 1.52–4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.


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